The Retroviral Diseases Section conducts translational clinical and laboratory research aimed at the development of novel therapies for HIV infection and AIDS-related malignancies. It also conducts laboratory research focused on an understanding of these diseases. During the past year, the group has investigated the role of a newly discovered herpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), in the pathogenesis of Kaposi's sarcoma (KS). We have found that this virus persists in the lymphocytes of patients receiving anti-herpes therapy. However, it is possible that replicating virus is important in the pathogenesis of KS, and a study is being planned to examine an anti-herpes drug in patients with KS and relatively high CD4 cells. In addition, we have developed a serologic assay to detect antibodies to a lytic antigen of this virus. We are conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma, including the anti-angiogenesis inhibitors TNP-470 and thalidomide, and paclitaxel. We have found that paclitaxel is one of the most active single drugs in patients with advanced KS. The response rate in this population is approximately 75%, and this includes several patients with pulmonary KS. In the laboratory, we are studying the differential ability of Th-1 and Th-2 T cells to be infected by HIV. In regard to anti-HIV therapy, we are conducting several laboratory studies of HIV protease and protease inhibitors. We have found that immature HIV virions produced in the presence of protease inhibitors do not go on to mature to infectious particles once the inhibitors are washed out. In addition, studies are underway to study the role of cysteines at positions 67 and 95 to the activity of HIV protease. We have found that lutathiolation of Cys 95 abolishes HIV protease activity, while glutathiolation of Cys 67 can enhance activity. This may provide a target for anti-HIV therapy. In the clinic, we are testing KNI-272, a novel HIV protease inhibitor; AZT plus bis-POM PMEA, a peptide HIV envelope vaccine; and beta-fluoro-ddA, a novel reverse transcriptase inhibitor.